There are currently few if any effective drug treatments for acute neural injuries (such as stroke and spinal cord injury) and chronic neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amytrophical lateral sclerosis, retinal degeneration, etc.). Accordingly, drugs that can protect neurons and/or promote neuroregeneration are urgently needed to treat these devastating injuries or diseases, as well as promote memory formation. Additional targets of interest include CaM Kinase II, which is involved in memory formation, and tyrosine phosphatase, which involved in such diseases as diabetes.
Neurotrophic growth factors (including e.g., nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, neurotrophin-4/5, ciliary neurotrophic factor, glial cell-derived neurotrophic factor, fibroblast growth factor and the like) have emerged in the past decade as promising drug candidates for treating acute and chronic neurodegenerative diseases. These protein neurotrophic growth factors play an essential role in the maintenance of neuronal populations from development through adulthood. However, clinical studies with these protein-based neurotrophic factors have proved to be disappointing due to their poor pharmacokinetic behavior, low bioavailability, inability to penetrate the brain, and pleiotropic effects. Therefore, much effort has been invested in the search for non-peptidyl small neurotrophic molecules.
Small neurotrophic molecules have the potential to be administered orally and to successfully traverse the blood/brain barrier. Unfortunately, however, few compounds have been identified thusfar which are promising enough to go to clinical trials (for reviews of this field, see e.g., Thoenen & Sendtner, Nat. Neurosci., 2002, Supplement 5:1046-1050; Saragovi & Gehring, Trends Pharmacol. Sci., 2000, 21:93-98; Xie & Longo, Prog. Brain Res., 2000, 128:333-347. Exemplary small neurotrophic molecules have been disclosed in PCT/US2004/021399, filed Jul. 2, 2004, published as WO2005/006945 on Jan. 27, 2005, and U.S. application Ser. No. 11/323,987, filed Dec. 30, 2005, published as USSN 2006/0160812 on Jul. 20, 2006, both of which are incorporated by reference in their entireties and for all purposes.
An abnormal rate of apoptosis may be responsible for at least some of the neuronal cell death in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (Thompson, Science, 1995, 267:1456-1462). Accordingly, without wishing to be bound by any theory, inhibitors of the apoptosis (and other forms of nerve cell death) pathways therefore can be used to promote neuronal survival. Peptide-based inhibitors of caspases, key enzymes in the apoptosis pathway, will suffer from the same drawback as neurotrophins in terms of their ability to cross the blood-brain barrier. Small molecule inhibitors of the apoptosis pathway are still in the early exploratory stage (for review, see Huang, Chem. & Biol., 2002, 9:1059-1072).